Method of reducing medical device related infections

ABSTRACT

The growth of microorganisms on catheters and other medical devices is inhibited by slime-inhibiting compounds. Slime-inhibiting compounds include salicylic acid and other NSAID.

This application is a continuation-in-part of application Ser. No.07/802,891, filed on Dec. 6, 1991, now abandoned.

BACKGROUND OF THE INVENTION

The frequency of infection associated with the use of invasive medicaldevices such as insertable as well as implantable devices is welldocumented. In the case of insertable devices such as catheters, therate of infection necessitates frequent replacement. In the case ofimplantable devices such as prosthetic devices, infections interferewith adaptation to the device. In either case, life-threateningsepticemia can result from such infections.

The pathophysiology of medical device related infections is complex.Many factors influence the risk and type of infection. These includefactors related to the host, to the medical device and to the virulenceand inoculum of the infecting organism. Hundreds of medical publicationshave investigated and documented the variables that contribute to thesefactors. It has been well established that the overwhelming majority ofmedical device associated infections occur when bacteria colonize andthen migrate along the medical device until they gain access to thebloodstream. Accordingly, the ability bacteria to adhere to a medicaldevice is important to the successful establishment of an infection.

The role of bacterial surface polysaccharides in adherence is wellestablished. Over 12 years ago a series experiments demonstrated theubiquitous nature of these polysaccharides. Surface polysaccharides arefound on most bacteria and fungi. When confronted with a specificlectin, the surface polysaccharides generate a glycoclyx that surroundsthe bacteria and adhering surface. The glycoclyx consists of a mass oflong polysaccharide fibers and appears to have several functions. It mayact as a source of nutrition for the bacteria. It may serve as aphysical barrier. Most importantly, surface polysaccharides determinethe specific surface interactions of the bacterial cell.

This phenomena has far reaching effects. For example the ability ofStreptococcus mutans to colonize teeth, Streptococcus salivarius tocolonize gums, Bacteroides fragilus to colonize the intestine, and GroupA streptococci to colonize the throat and skin are all manifestations ofa complex interaction between specific surface polysaccharides andspecific lectins, which are proteins that bind to specificpolysaccharides.

The importance of bacterial surface and medical device relatedinfections is best illustrated by coagulase negative staphylococci. S.epidermidis, the most important and common of the coagulase negativestaphylococci, was previously considered a non-pathogenic organism. Ithas now emerged as the most common cause of foreign body infection andnosocomiai sepsis. It is the major cause of prosthetic valveendocarditis, vascular graft infection, artificial hip and kneeinfection, and catheter related sepsis. Although less virulent than S.aureus and many other bacteria, it is highly resistant to mostantimicrobials except vancomycin and rifampin.

In the early 1980's, electron microscopy studies demonstrated thatcertain strains of S. epidermidis produce an extracellular slime likesubstance. The extracellular slime is a complex substance composedmostly of polysaccharide.

The production of a surface polysaccharide biofilm or slime by anorganism enables it to adhere to surfaces of insertable or implantabledevices and cause infection. The slime appears to contain a galactoserich polysaccharide "adhesive" which mediates attachment of the organismto polymers. It also contains a polysaccharide substance thataccumulates after adherence occurs and cements the organism to themedical device.

Besides adhesion, the slime appears to have other functions. It binds toglycopeptide antibiotics including vancomycin. This may explain why mostS. epidermidis infections do not respond to antimicrobial therapy alone.When infection occurs on an inserted or implanted device, removal of thedevice is usually required. Slime also interferes with certain immuneresponses.

The extracellular slime of S. epidermidis is really a manifestation ofexuberant production of surface polysaccharide. The quantitativeproduction appears to be regulated by a complex mechanism that turns onand off production based upon the local environment. Although S.epidermidis has been the focus of much of the research on foreign-bodyinfections, this concept has been studied in other organisms.Colonization by pseudomonas species on the interior surface of PVC andother pipes has demonstrated a glycocalyx mass that shields organismsfrom disinfectants including chlorine, phenolics, quaternary-ammonium,and iodophor disinfectants. Once a bacterial glycocalyx is formed, it isvery difficult to break down.

The development of polymers that contain antimicrobial properties hasimportant implications for both medicine and industry. Aside fromfactors related to bacterial polysaccharides, the coating of the foreignbody by proteins (albumin, fibronectin, platelets) from the host, aswell as a variety of factors related to the polymer itself undoubtedlyaffect the risk of infection.

Several approaches have been utilized to produce medical devices made ofor with polymers with antimicrobial properties, as described, forexample, in U.S. Pat. Nos. 4,769,013, 4,713,402 and 4,886,505.Antimicrobial agents can be incorporated during the production processor grafted into the surface as described in U.S. Pat. No. 4,925,668.However, even broad-spectrum antibiotics eventually lead to theselection of resistant organisms. Selection of opportunistic fungi,resistant gram negative rods, S. epidermidis, and enterococci is likely.In addition, unless the "delivery" of the antibiotic is rapid, potent,and long lasting, formation of the protective glycocalyx will preventits effectiveness. In addition, many antibiotics produce allergicreactions in some patients.

The present invention is based on an alternative approach, namelyinterference with the adherence of bacteria to polymeric surfaces ofmedical devices. Studies have demonstrated that both the degree of slimeand adhesive production influence and correlate with the degree ofbacterial adherence to silastic catheters. S. haemolyticus, unlike S.epidermidis do not produce slime and are a very uncommon cause ofcatheter related infection. As described herein, substances that preventor reduce the production of slime by bacteria reduce their adherence andthus reduce the level of growth of microorganisms on the surface of theinserted or implanted devices.

It has been observed that sodium salicylates and certain other compoundscan interfere with the production of capsule polysaccharide productionin Klebsiella pneumonia. Salicylate binds to lipids in the outermembrane where biosynthetic enzymes are located. It has been postulatedthat capsular polysaccharide is the backbone of glycocalyx formation.

An object of the present invention is to use salicylates and othernonsteroidal anti-inflammatory drugs ("NSAID"), as well as othercompounds such as chelating agents, to prevent the production of slimeor surface polysaccharides in target microorganisms, thereby preventingtheir adherence and growth on materials used in medical devices.

A further object of the present invention is to utilize slime orsurface-polysaccharide-inhibiting compounds which have, in addition,anti-platelet and thrombotic properties. This is particularly usefulsince the formation of the glycocalyx may be determined in part byplatelets and fibronectin. The use of such compounds may decrease theincidence of thrombophlebitis as well as infection.

It is a further objective of the present invention to reduce bacterialgrowth on implanted devices using compounds that are relativelynon-toxic.

These and other objectives are accomplished by the invention describedin detail below.

SUMMARY OF THE INVENTION

As embodied herein, the foregoing and other objects are achieved by thepresent invention which involves the use of salicylic acid and othersimilarly-acting compounds to inhibit the formation of microbial slimeor surface polysaccharides, thus interfering with their ability toadhere to invasive medical devices and thereby cause infection.

DETAILED DESCRIPTION OF THE INVENTION

Described herein is a method for preventing the adherence and growth ofmicroorganisms on catheters as well as other insertable or implantablemedical devices using slime-inhibiting compounds. Reduction of the slimeproduction by such microorganisms reduces their ability to adhere to themedical device thus reducing the risk of infection and nosocomialsepsis.

The present invention is based on the discovery that by inhibiting theadherence of bacteria to catheters and other medically related foreignbodies, the risk of infection and sepsis can be reduced, and theresidence time in which the medical device can remain in the body can beincreased. The adherence of the bacteria to the medical device isinhibited by using a compound that interferes with the ability of themicroorganism to produce a slime. The term slime, as used herein,includes the extracellular and capsular substance, composed to a largeextent of extracellular polysaccharide, which is produced by manymicroorganisms, including coagulase negative staphylococci such as S.epidermidis and S. aureus, Escherichia coli, pseudomonas and other gramnegative rods, as well as other microorganisms.

A slime-inhibiting compound is a substance or collection of substanceswhich inhibits either production of the slime produced by amicroorganism, or a component of the slime, such as the polysaccharidecomponent. Regardless of the component of the slime that it inhibits,the slime-inhibitor reduces the ability of a microorganism to adhere toa polymeric surface. Slime inhibiting compounds include, but are notlimited to, NSAID such as acetylsalicylic acid (aspirin), salicylate,bis-salicylate, benzyl-benzoic acid, diflunisal, fendosal, indomethacin,acemetacin, cinmetacin, sulindac, tolmetin, zomepirac, diclofenac,fenclofenac, isoxepac, ibuprofen, flurbiprofen, naproxen, ketoprofen,fenoprofen, benoxaprofen, indoprofen, pirprofen, carprofen, mefenamicacid, flufenamic acid, meclofenamate, niflumic acid, tolfenamic acid,flunixin, clonixin, phenylbutazone, feprazone, apazone, trimethazone,mofebutazone, kebuzone, suxibuzone, piroxicam, isoxicam and tenoxicam,as well as chelating agents.

As contemplated herein, medically implanted or inserted devices includethose inserted percutaneously or through an orifice, or implanted forshort or long ranges of time as well as permanently. Such devicesinclude catheters as well as sutures, heart valves, grafts such asvascular or other tissue grafts and prosthetic devices such asartificial hips and knees, lenses including contact (both hydrophilicand gas permeable) and intraocular lenses, surgical staples, and dentalarea implants. Such devices are generally made of a polymeric materialsuch as silastic or other silicone-based material, pollyethylenetecephtalate (PET), dacron, knitted dacron, velour dacron, polyglacin,chromic gut, nylon, silk, bovine arterial graft, polyethylene (PE),polyurethane, polyvinyl chlorides silastic elastomer, silicone rubber,PMMA [poly-(methyl methacrylate), latex, polypropylene (PP), titanium,cellulose, poly vinyl] alcohol (PVA), poly (hydroxyethyl methacrylate(PHEMA), poly (glycolic acid), poly (acrylonitrile) (PAN),floroethylene-cohexafluoropropylene (FEP), teflon (PTFE) and Co-Cralloys.

The slime inhibitor may be added to the material on which microbialgrowth is to be inhibited by spraying, dipping, soaking, or byincorporation into the material itself. Alternatively, the inhibitor maybe incorporated into a secondary polymer used to coat the surface of themedical device. Such a secondary polymer may have slow releaseproperties that allow for the gradual release of the inhibitor into themicroenvironment of the device.

Several of the slime-inhibitors used to practice the present inventionhave additional therapeutic properties. Accordingly, their use is oftensuggested in conjunction with medical implants, ostensibly to decreaseswelling around the site of implantation. For example, in U.S. Pat. No.4,769,013 the use of salicylate as an analgesic or anesthetic inconjunction with a medical material is suggested. In addition, drugsdescribed herein have been incorporated into drug delivery devicesbecause of their therapeutic properties. However, the level of compoundused in such circumstances must be relatively high to achieve thedesired therapeutic result.

In contrast, and because the present invention contemplates use of alevel of compound sufficient only to inhibit slime formation within themicroenvironment of the device, the levels of the compounds describedherein are below the level necessary for therapeutic systemic effect.Generally, the amount of inhibitor utilized herein to prevent productionof polysaccharide production and adherence to the device, as measured byconcentration on the surface of the device, is between about 1 and about20 mM. This level is believed to be sufficient to decrease the incidenceof thrombophlebitis associated with the device due to the knownanti-platelet activity of NSAID.

According to one preferred embodiment, distribution of the inhibitor onthe device to be inserted or implanted is accomplished by incubating thedevice in a solution containing the slime-inhibitor. The inhibitor issuspended in a solution, most preferably an alcohol-based solution, at aconcentration of between about 1 mM and 1 M. The device is incubatedwithin such a solution for between about 15 minutes and 24 hours at atemperature of between about -20° C. to 25° C. after which it is airdried.

Preferably the coating is performed at between about -20° C. and 10° C.In general, use of the inhibitor in conjunction with alcohol has beenfound to increase the polysaccharide inhibiting properties. When thesurface to be treated is teflon, however, the alcohol decreases theeffectiveness of the slime-inhibitor. When alcohol is used, optimumresults are often obtained by incubating at -20° C.

Another method makes use of tridodecylemthylammonium chloride (TDMAC) orbenzalkonium chloride to bind the slime-inhibiting substance to thecatheter or medical device. TDMAC has previously been used to coatcatheters and other medical devices with antibiotics and heparin.

The ability of a compound to inhibit the production of slime by amicroorganism and thereby inhibit its growth on a medically insertableor implantable device can be measured by several methods. Once thedevice is coated or impregnated with the compound, the device is exposedto a source of bacteria over a specified period of time, after which thedevice is washed and the growth of the bacteria on the device measured.Such measurements may include colony counts or other means ofquantifying microorganisms, such as chemiluminescent or bioluminescentassay, which monitor a particular metabolite as a means of quantifyingbacterial load or by radiolabelling techniques.

A suitable methodology for analyzing the effectiveness of an inhibitorin preventing microbial growth on catheters or other medicallyinsertable or implantable devices is described in Example 21.

Although the current application deals with medical devices, thisconcept can be applied in a number of industrial areas. Glycocalyxformation by gram negative rods occurs in PVC and other plumbingsupplies. The formation of this glycocalyx has been shown to contaminatethe manufacturing process of products in which sterility is vital.Coating such pipes with a NSAID may minimize this problem.

In addition, similar applications can be considered in the marineindustry where water-borne organisms cause destruction. Alsocontemplated by the present invention is the use of the NSAID asadditives to waterproofing and coatings for boats and other marinesupplies.

EXAMPLES Example 1

The effect of sodium salicylate on the growth characteristics of variousorganisms was studied. A slime producing strain of coagulase negativestaphylococcus was grown in increasing concentrations of salicylate intwo different types of media, chemically defined media (CDM) andtripticase soy proth (TSB). The resultant bacterial counts were asfollows:

    ______________________________________                                                     CDM    TSB                                                       ______________________________________                                        Control        2.3 × 10.sup.9                                                                   1.2 × 10.sup.9                                   1 mM          7.2 × 10.sup.8                                                                   1.4 × 10.sup.9                                   5 mM          8.3 × 10.sup.8                                                                   5.7 × 10.sup.8                                  10 mM          5.7 × 10.sup.8                                                                   5.2 × 10.sup.8                                  25 mM          2.3 × 10.sup.8                                                                   3.2 × 10.sup.7                                  ______________________________________                                    

These studies demonstrated that salicylate does not have antimicrobialproperties. It did not inhibit the growth of coagulase negativestaphylococci in either chemically defined media or in commerciallyprepared tryticase soy broth. Similar growth curves were obtained withgram negative rods including E. coli and pseudomonas.

Example 2

As a crude measure of its ability to influence the production of slime,the yield of slime by weight from a one liter broth culture S.epidermidis grown in the presence of increasing concentrations ofsalicylate was used to measure the ability of salicylate to influencethe production of slime.

    ______________________________________                                               Concentration                                                                           Yield                                                        ______________________________________                                               Control   86 mg.                                                              1 mM      68 mg.                                                              5 mM      58 mg.                                                              25 mM     47 mg.                                                       ______________________________________                                    

As noted, the amount of slime decreased with increasing concentrationsof salicylate.

Example 3

The effect of increasing concentrations of salicylate on the productionof slime by S. epidermidis was measured by using a spectrophotometricassay. The results were as follows:

    ______________________________________                                        Concentration (mM)                                                                             Optical Density                                              ______________________________________                                        Control          1.5                                                          1 mM             1.4                                                          2 mM             1.3                                                          5 mM             .5                                                           10 mM            .08                                                          25 mM            .01                                                          ______________________________________                                    

A progressive fall in the optical density with increasing concentrationsof salicylate, most evident at 5 mM and above, was observed.

Example 4

Selected strains of slime-producing coagulase negative staphylococci (S.epidermidis) were grown in various concentrations of salicylate. After24 hours growth, various types of catheters were placed in highconcentrations of the organisms for 15 minutes. This assay exposed thecatheters to a high concentration of organisms for a short period oftime. The catheters were washed three times, and rolled onto agar in astandardized manner. The agar plates were incubated overnight, and thenumber of colonies counted. The percent inhibition of adherence wascalculated with the following formula: ##EQU1## with the followingresults:

    ______________________________________                                                       Adherence                                                      Concentration  (CFU plate)                                                                              Inhibition                                          ______________________________________                                        Polyurethane                                                                  0              229                                                            1 Mm           236        N.I.                                                2 Mm            48        79%                                                 Teflon                                                                        0              171                                                            1 mM            50        71%                                                 5 mM            22        87%                                                 Silastic                                                                      0              325                                                            1 mM           265        19%                                                 2 mM           149        54%                                                 25 mM           77        76%                                                 PVC                                                                           0              378                                                            1 mM           157        58%                                                 4 mM            85        85%                                                 ______________________________________                                    

Example 5

A similar assay to that used in Example 4 was performed using S. aureusand E. coli. This was done using a silastic catheter. The results wereas follows:

    ______________________________________                                                Adherence    Adherence                                                        (CFU/plate)  (CFU/plate)                                              Concentration                                                                           E. coli  % Inhib.  S. aureus                                                                             % Inhib.                                 ______________________________________                                        0         90                 285                                              1 mM      32       64        154     46%                                      5 mM      .5       99        112     61%                                      ______________________________________                                    

This demonstrated an effect with E. coli and S. aureus that was similarto that observed with S. epidermidis.

Example 6

Catheter segments were incubated overnight in salicylate and compared tocontrol catheters that were not incubated in salicylate to determinewhether the salicylate would coat the polymer surface.

Catheter segments were incubated in 100 mM salicylate overnight at 37°C., pH 7.0. The catheters were then dried, and dipped into a 5×10⁵CFU/ml coagulase negative staphylococci for 15 minutes. All studies weredone in triplicate.

    ______________________________________                                        Adherence (CFU/plate)                                                                  Control   Salicylate                                                                              Inhib.                                           ______________________________________                                        Silastic   600         317       47%                                          Polyurethane                                                                             33          20        27%                                          Teflon     35          13        63%                                                     17           3        82%                                          PVC        85          50        41%                                          ______________________________________                                    

Example 7

Teflon, PVC, and silastic catheters were incubated in 100 mM salicylateat 37° overnight and were incubated with high concentrations of bacteria(10⁷ -10⁸ CFU/ml). After incubation, the catheters were washed threetimes, then rolled onto agar and incubated. The colonies were counted.The results were as follows:

    ______________________________________                                                  Teflon     PVC    Silastic                                          ______________________________________                                        E. coli                                                                       Control      8.0         13     211                                           Salicylate  13.0          9     103                                           Inhibition   0%          29%    51%                                           P. aeruginosa                                                                 Control     80           275     59                                           Salicylate   1           200     3                                            Inhibition  100%         27%    94%                                           ______________________________________                                    

The inhibition was most obvious with pseudomonas regardless of the typeof polymer used. The E. coli did not adhere as well as pseudomonasregardless of the catheter type.

Example 8

A study similar to that described in Example 7 was done with a smallerinoculum of (10⁵ CFU/ml) of S. aureus with the results as follows:

    ______________________________________                                                     Adherence                                                                     CFU/plate)                                                                             Inhibition                                              ______________________________________                                        Teflon                                                                        Control        147                                                            Salicylate      54        63%                                                 PVC                                                                           Control        192                                                            SAL            136        30%                                                 Silastic                                                                      Control        296                                                            SAL            224        24%                                                 ______________________________________                                    

Example 9

Silastic and polyurethane catheters were incubated in 95% EtOH and 95%EtOH and 200 mM salicylate at pH 7.0 for 2 hours at -20° C. Thecatheters were air dried and incubated in broth containing 10⁵ CFU/ml S.epidermidis for 15 minutes at 37° C. The catheters were then washed androlled onto agar. The results on two identical experiments were asfollows:

    ______________________________________                                                 Control   Salicylate                                                                              Inhibition                                       ______________________________________                                        Trial I                                                                       Polyurethane                                                                             143         91        36%                                          Silastic   461         35        92%                                          Trial 2                                                                       Silastic    37         .67       98%                                          PVC         60         50        17%                                          Teflon      19         20         0%                                          Polyurethane                                                                             138         57        59%                                          ______________________________________                                    

Example 10

Similar experiments to those described in Example 9 were conducted usingE. coli. A high concentration of organisms (10⁶) was used. Cathetersegments were incubated for 2 hours in 200 mM salicylate in 95% ethanol.The catheters were dried and placed in the E. coli cultures at roomtemperature. They were allowed to incubate for 18 hours. The resultswere as follows:

    ______________________________________                                        (CFU/plate)                                                                   Catheter   Control     Salicylate                                                                              Inhibition                                   ______________________________________                                        Polyurethane                                                                             77          10        88%                                          PVC        21          3         86%                                          Silastic   50          3         96%                                          ______________________________________                                    

Example 11

Silastic catheters prepared as described in Example 9 were incubated incultures of S. epidermidis for three days at 37° C.

    ______________________________________                                        CFU/plate                                                                     Control        Salicylate                                                                              Inhibition                                           ______________________________________                                        15             6         60%                                                  ______________________________________                                    

Example 12

Silastic catheters prepared as described in Example 9 were incubated incultures of E. coli for three days. (10⁵ CFU/ml ).

    ______________________________________                                        CFU/plate                                                                     Control        Salicylate                                                                              Inhibition                                           ______________________________________                                        1400           700       50%                                                  ______________________________________                                    

Example 13

Polyurethane and silastic catheters were soaked overnight in varyingconcentrations of salicylic acid in ethanol at -20° C. and then exposedto coagulase negative staphylococci and E. coli for 4 hours at 37° C.They were washed and rolled as per the protocol described in Example 9.

    ______________________________________                                                  pH      Count/Plate                                                                              CFU/mm                                           ______________________________________                                        Coagulase Negative Staphylococci (Polyurethane - tubing)                      Control     7.33      >400       20.0                                         Salicylate 200 mM                                                                         7.19      310        14.6                                         Salicylate 600 mM                                                                         6.77       50         2.4                                         Ibuprofen 400 mM                                                                          7.22      233        11.5                                         Ibuprofen 200 mM                                                                          7.02      352        18.1                                         E. coli (silastic tubing)                                                     Control               250        12.0                                         Salicylate 200 mM     226        11.6                                         Salicylate 600 mM      32         1.6                                         Ibuprofen 400 mM      238        12.0                                         Ibuprofen 200 mM      185         9.6                                         ______________________________________                                    

Example 14

Catheters treated with salicylate and ibuprofen as described in Example9 were incubated in phosphate buffered saline having a concentration of10³ CFU/ml E. coli for six days at 37° C. This produced a constantconcentration of organisms.

    ______________________________________                                        Coating          (CFU/plate)                                                                             Inhibition                                         ______________________________________                                        Control          240                                                          200 mM salicylate                                                                              121       50%                                                100 mM Ibuprofen  70       71%                                                ______________________________________                                    

Despite six days of incubation, the inhibition was impressive. It wasgreater with ibuprofen than salicylate in this experiment.

Example 15

Polyurethane and silastic catheters were incubated in ibuprofen,acetyl-salicylate, and benzoyl-benzoic acid with 95% ethanol for 2hours. The catheters were then incubated in S. epidermidis as describedin Example 9. The results were as follows:

    ______________________________________                                                         CFU/plate)                                                                             Inhibition                                          ______________________________________                                        Polyurethane                                                                  Control            295                                                        Acetyl-Salicylate (200 mM)                                                                       127        57%                                             Salicylate (200 mM)                                                                              270         9%                                             Ibuprofen (100 mM) 166        44%                                             Benzyl benzoic (100 mM)                                                                          333         0%                                             Silastic                                                                      Control             52                                                        Acetyl-Salicylate (200 mM)                                                                        7         86%                                             Salicylate (200 mM)                                                                               33        36%                                             Benzyl benzoic (100 mM)                                                                           9         83%                                             ______________________________________                                    

Example 16

Polyurethane catheters were preheated overnight at 67° C. and coated inthe compounds listed below at -20° C. in 95% ethanol. They were thenincubated in coagulase negative staphylococci at 37° for 18 hours, andwashed three times in phosphate buffered saline. ATP was extracted withextralight and read with firelight in a dynatech luminometer reader.

    ______________________________________                                                   Units of light (measured at 48°)                            ______________________________________                                        Control      .62                                                              Salicylate   .19                                                              Acetylsalicylate                                                                           .06                                                              Acetaminophen                                                                              2.4                                                              Ibuprofen    .32                                                              Phenylbutazone                                                                             .02                                                              Indomethacin .07                                                              ______________________________________                                    

The units of light are a reflection of the amount of ATP released andbacteria that have adhered to the polymer. The experiment was repeated,but by growing the organisms directly in the microlite wells. Culturesof coagulase negative staphylococci were grown in the presence of 2 mMNSAID in microlite wells, washed and treated with extralight andfirelight.

    ______________________________________                                                   Units of light (measured at 48°)                            ______________________________________                                        Control      89.0                                                             Acetylsalicylate                                                                           13.0                                                             Salicylate   15.0                                                             Ibuprofen    9.0                                                              Acetaminophen                                                                              108.0                                                            Indomethacin 9.2                                                              Phenylbutazone                                                                             19.1                                                             ______________________________________                                    

Example 17

Several experiments were done with gram negative rods in urine insteadof broth. Silastic catheters were prepared as previously described andwere incubated for 4-5 hours at 37° C. All studies were done in triplet.

    ______________________________________                                        Silastic Catheter   CFU/mM     Inhibition                                     ______________________________________                                        E. coli Incubated in Urine (5 Hours)                                          Control             25.0                                                      Salicylic Acid (200 mM)                                                                           17.0       31%                                            Salicylic Acid (600 mM)                                                                           1.5        94%                                            Klebsiella pneumoniae (4 Hours)                                               Control             14.0                                                      Salicylic Acid (200 mM)                                                                           4.9        65%                                            Salicylic Acid (600 mM)                                                                           1.8        87%                                            E. Aerogenes in Urine (5 Hours)                                               Control             15.5                                                      Salicylic Acid (200 mM)                                                                           9.8        37%                                            Salicylic Acid (600 mM)                                                                           4.3        73%                                            ______________________________________                                    

Example 18

In an attempt to determine the length of the observed effect, silasticcatheters were incubated in salicylic acid as described, and then placedin sterile urine for 4 days. At the end of this period, the catheterswere removed and then placed in a broth culture of E. coli. Results arethe mean of three trials.

    ______________________________________                                        Silastic Catheter CFU/mM    Inhibition                                        ______________________________________                                        Control           13.2                                                        Salicylic Acid (200 mM)                                                                         9.6       27%                                               Salicylic Acid (600 mM)                                                                         2.9       78%                                               ______________________________________                                    

This experiment demonstrated that the coating is not lost immediatelyafter the catheter is placed in an aqueous solution.

Example 19

S. epidermidis was radiolabeled by including 1 μCi of (¹⁴ C - sodiumacetate) in the preliminary overnight culture. The catheter segmentswere exposed to the broth culture overnight at 37° C. The catheters werevigorously washed in saline, air dried, and placed in scintillationvials for counting.

    ______________________________________                                        TSB with NaAc (1.2 - .sup.14 C)                                               Overnight at 37° C.                                                    Silastic Catheter  CPM                                                        ______________________________________                                        Control            1481.0                                                     Salicylic Acid (200 mM)                                                                          528.0                                                      Salicylic Acid (600 mM)                                                                          165.0                                                      ______________________________________                                    

Example 20

Another embodiment uses tridodecylemthylammonium chloride (TDMAC) orbenzalkonium chloride which coats the catheters and also binds to thesalicylates. Silastic catheters that had been preheated were coated in5% TDMAC in ethanol for 40 minutes at room temperature. The cathetersegments were vigorously washed with sterile water and air dried. Thesegments were then immersed in ethanol, 200 mM salicylic acid and 600 mMsalicylic acid overnight at -20° C. The catheters were air dried andimmersed in a trypticase soy broth culture of E. coli or S. epidermidisat 37° C. Catheters were washed 3 times in 3 changes of sterile salineand rolled on Mueller-Hinton Agar plates. The plates were incubatedovernight at 37° C. and the colonies were counted.

    ______________________________________                                                          CFU/  CFU/                                                                    Plate mM      Inhibition                                    ______________________________________                                        E. coli (5 Hour Incubation)                                                   Control             143.0   6.5                                               Salicylic Acid (200 mM)                                                                           23.0    1.1     83%                                       Salicylic Acid (600 mM)                                                                           1.5     0.07    99%                                       S. epidermidis (Overnight Incubation)                                         Control             91.0    4.3                                               Salicylic Acid (200 mM)                                                                           81.0    3.9      9%                                       Salicylic Acid (600 mM)                                                                           52.0    2.6     40%                                       ______________________________________                                    

Example 21

The following is a recommended method for determining whether aparticular compound inhibits slime production and adherence to a medicaldevice:

1. Prepare test coating solutions at desired concentrations. Preparesterile 3 cm section of tubing.

2. Incubate tubing pieces in sterile water at 67° C. overnight, dry 1hour, then expose to test solutions and controls at -20° C. for 2 hours.Ensure that all tubing are immersed in solution.

3. Remove the tubing and dry coated samples in a sterile field. Marktubing 1 cm from end.

4. Assemble a sterile 3 cm syringe with a sterile industrial bluntsyringe which will fit securely into the tubing to be tested.

5. Attach the marked end of the 3 cm lengths of coated tubing to theneedle. Withdraw the plunger from the syringe to about the 2 or 3 ccmark.

6. Place 15 ml of a 10⁶ bacterial suspension into a sterile 50 cc tubeand place up to 3 tubes into each tube. Incubate at 37° C. for 15minutes. The length of incubation and inoculum size can be varied.

7. Transfer each tubing segment into a separate 15 ml sterile tubecontaining approximately 5 ml of sterile saline. Each tube is vigorouslywashed by drawing saline back and forth through the tube 3 times.

8. The process is repeated until a total of 3 washes in 3 separatesaline tubes is completed.

9. A 1 cm segment of the distal catheter is cut off and discarded.

10. The remaining 2 cm section was quantitatively rolled over a bloodagar plate in 4 directions. The plates are incubated overnight a 37° C.and the colonies are counted.

11. The catheter segments are carefully measured so that the number ofCFU/mm catheter can be calculated.

I claim:
 1. An insertable or implantable medical device havingdistributed thereon an effective concentration of a biofilm-inhibitingcompound that is sufficient to cause an effect on microbial biofilm inthe microenvironment of a surface of said device, but whichconcentration is otherwise insufficient to cause a substantialtherapeutic systemic effect in an organism in which said device isimplanted or inserted.
 2. An insertable or implantable medical devicehaving reduced risk of causing infection after insertion or implantationcomprising a device having distributed thereon between about 1 and 20milliMolar surface concentration of a surface polysaccharide biofilminhibiting compound.
 3. A device according to claim 1 wherein saiddevice is comprised of a polymer selected from the group consisting ofsilastic or other silicone-based material, polyethylene tecephtalate(PET), polyglacin, polydioxanone, chromic gut, nylon, silk, dacron,knitted dacron, velour dacron, bovine arterial graft, polyethylene (PE),polyvinyl chloride (PVC), silastic elastomer, silicone rubber, PMMA,latex, polypropylene (PP), titanium, cellulose, polyvinyl alcohol (PVA),poly-(hydroxyethyl methacrylate) (PHEMA), poly-(glycolic acid), poly(acrylonitrile) (PAN), floroethylene-co-hexafluoropropylene (FEP),teflon (PTFE), Co-Cr alloys, polyurethane, polyester,polytetrafluoroethylene, and biological polymers such as collagen.
 4. Adevice according to claim 1 wherein said slime-inhibiting compound is achelating agent.
 5. A device according to claim 1 wherein said surfacepolysaccharide biofilm inhibiting compound is a NSAID.
 6. A deviceaccording to claim 5 wherein said NSAID is selected from the groupconsisting of salicylic acid, acetylsalicylic acid (aspirin),bis-salicylate, benzyl-benzoic acid, diflunisal, fendosal, indomethacin,acemetacin, cinmetacin, sulindac, tolmetin, zomepirac, diclofenac,fenclofenac, isoxepac, ibuprofen, flurbiprofen, naproxen, ketoprofen,fenoprofen, benoxaprofen, indoprofen, pirprofen, carprofen, mefenamicacid, flufenamic acid, meclofenamate, niflumic acid, tolfenamic acid,flunixin, clonixin, phenylbutazone, feprazone, apazone, trimethazone,mofebutazone, kebuzone, suxibuzone, piroxicam, isoxicam and tenoxicam.7. A device according to claim 6 wherein said NSAID is salicylic acid ora salt thereof.
 8. A device according to claim 6 wherein said NSAID isibuprofen.
 9. An insertable or implantable medical device having reducedrisk of causing thrombophlebitis after insertion or implantationcomprising a device having distributed thereon an effective amount of aNSAID insufficient to cause a substantial therapeutic systemic effect.10. An insertable or implantable medical device having reduced risk ofcausing thrombophlebitis after insertion or implantation comprising adevice having distributed thereon between about 1 and 20 milliMolarsurface concentration of a NSAID.
 11. A device according to claim 9wherein said NSAID is selected from the group consisting of salicylicacid, acetylsalicylic acid (aspirin), bis-salicylate, benzyl-benzoicacid, diflunisal, fendosal, indomethacin, acemetacin, cinmetacin,sulindac, tolmetin, zomepirac, diclofenac, fenclofenac, isoxepac,ibuprofen, flurbiprofen, naproxen, ketoprofen, fenoprofen, benoxaprofen,indoprofen, pirprofen, carprofen, mefenamic acid, flufenamic acid,meclofenamate, niflumic acid, tolfenamic acid, flunixin, clonixin,phenylbutazone, feprazone, apazone, trimethazone, mofebutazone,kebuzone, suxibuzone, piroxicam, isoxicam and tenoxicam.
 12. A deviceaccording to claim 1 which further comprises a surface polysaccharidebiofilm-inhibiting compound incorporated in the material used to makesaid device.
 13. A device according to claim 2 wherein said device iscomprised of a polymer selected from the group consisting of silastic orother silicone-based material, polyethylene tecephtalate (PET),polyglacin, polydioxanone, chromic gut, nylon, silk, dacron, knitteddacron, velour dacron, bovine arterial graft, polyethylene (PE),polyvinyl chloride (PVC), silastic elastomer, silicone rubber PMMA[poly-(methyl methacrylate)], latex, polypropylene (PP), titanium,cellulose, polyvinyl alcohol (PVA), poly-(hydroxyethyl methacrylate)(PHEMA), poly-(glycolic acid), poly (acrylonitrile) (PAN),floroethylene-co-hexafluoropropylene (FEP), teflon (PTFE), Co-Cr alloys,polyurethane, polyester, polytetrafluoroethylene, and biologicalpolymers such as collagen.
 14. A device according to claim 2 whereinsaid surface polysaccharide biofilm-inhibiting compound is a cheletingagent.
 15. A device according to claim 2 wherein said surfacepolysaccharide biofilm-inhibiting compound is a NSAID.
 16. A deviceaccording to claim 15 wherein said NSAID is selected from the groupconsisting of salicylic acid, acetylsalicylic acid (aspirin),bis-salicylate, benzyl-benzoic acid, difunisal, fendosal, indomethacin,acemethacin, cinmetacin, sulindac, tolmetin, zomepirac, diclofenac,fenclofenac, isoxepac, ibuprofen, flurbiprofen, naproxen, ketoprofen,fenoprofen, benoxaprofen, indoprofen, pirprofen, carprofen, mefenamicacid, flufenamic acid, meclofenamate, niflumic acid, tolfenamic acid,flunixin, clonixin, phenylbutazone, feprazone, apazone, trimethazone,mofebutazone, kebuzone, suxibuzone, piroxicam, isoxicam and tenoxicam.17. A device according to claim 16 wherein said NSAID is salicylic acidor a salt thereof.
 18. A device according to claim 16 wherein said NSAIDis ibuprofen.
 19. A device according to claim 10 wherein said NSAID isselected from the group consisting of salicylic acid, acetylsalicylicacid (aspirin), bis-salicylate, benzyl-benzoic acid, diflunisal,fendosal, indomethacin, acemetacin, cinmetacin, sulindac, tolmetin,zomepirac, diclofenac, fenclofenac, isoxepac, ibuprofen, flurbiprofen,naproxen, ketoprofen, fenoprofen, benoxaprofen, indoprofen, pirprofen,carprofen, mefenamic acid, flufenamic acid, meclofenamate, niflumicacid, tolfenamic acid, flunixin, clonixin, phenylbutazone, feprazone,apazone, trimethazone, mofebutazone, kebuzone, suxibuzone, piroxicam,isoxicam and tenoxicam.
 20. A device according to claim 1 selected fromthe group consisting of a contact lens, an intraocular lens, a suture, astaple, a catheter, a heart valve, a graft, a prosthetic device and adental area implant.
 21. A device according to claim 2 selected from thegroup consisting of a contact lens, an intraocular lens, a suture, astaple, a catheter, a heart valve, a graft, a prosthetic device and adental area implant.